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Use of Completion Lymph Node Dissection for Sentinel Lymph Node-Positive Melanoma
Journal Pre-proof Use of Completion Lymph Node Dissection for Sentinel Lymph Node Positive Melanoma Joshua N. Herb, MD, Lisette N. Dunham, MSPH, David W. Ollila, MD, FACS, Karyn B. Stitzenberg, MD, MPH, FACS, Michael O. Meyers, MD, FACS PII:
S1072-7515(20)30071-5
DOI:
https://doi.org/10.1016/j.jamcollsurg.2019.12.010
Reference:
ACS 9703
To appear in:
Journal of the American College of Surgeons
Received Date: 16 December 2019 Accepted Date: 16 December 2019
Please cite this article as: Herb JN, Dunham LN, Ollila DW, Stitzenberg KB, Meyers MO, Use of Completion Lymph Node Dissection for Sentinel Lymph Node Positive Melanoma, Journal of the American College of Surgeons (2020), doi: https://doi.org/10.1016/j.jamcollsurg.2019.12.010. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 by the American College of Surgeons. Published by Elsevier Inc. All rights reserved.
1 Use of Completion Lymph Node Dissection for Sentinel Lymph Node Positive Melanoma Joshua N Herb, MDa, Lisette N Dunham, MSPHb, David W Ollila, MD, FACSa,b, Karyn B Stitzenberg, MD, MPH, FACSa,b, Michael O Meyers, MD, FACSa,b a
Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC b
Disclosure Information: Nothing to disclose. Support: Dr Herb is supported by a National Service Research Award Pre-Doctoral/PostDoctoral Traineeship from the Agency for Healthcare Research and Quality sponsored by the Cecil G Sheps Center for Health Services Research, University of North Carolina at Chapel Hill, Grant No. 5T32 HS000032. Presented at the 131st Annual Meeting of the Southern Surgical Association, Hot Springs, VA, December 2019 Corresponding Author Information: Joshua Herb, MD Division of Surgical Oncology, CB#7213 UNC Department of Surgery Chapel Hill, NC, 27599 Email: [email protected] Brief Title: Lymph Node Dissection in Melanoma
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Background: For patients with sentinel node positive melanoma (SNPM), randomized trials, first reported in 2015, show no benefit for routine completion lymph node dissection (CLND) in selected patients. This study examines time trends in CLND and explores institutional and clinical factors associated with CLND. Study Design: The National Cancer Database was queried for patients > 18 years old from 20122016 with SNPM. A high-volume center was defined as >80th percentile for number of sentinel node procedures. Poisson regression assessed temporal trends, and identified patient, pathologic, and institutional characteristics associated with CLND. Results: From 2012-2016, 7146 patients with SNPM were identified. The proportion of patients undergoing CLND was steady in years 2012-2014 (61-63%), but decreased to 57% in 2015 and 50% in 2016 (p<0.0001). The proportion of patients with SNPM who underwent CLND decreased over time for both high (66% to 52%, p<0.0001) and lower volume centers (55% to 45%, p=0.06). Female sex (RR 0.97, p<0.001) and increasing age (RR 0.98, p<0.0001) were associated with lower likelihood of CLND. Increased Breslow depth (RR 1.015, p=0.006), ulceration (RR 1.067, p=.02), and high-volume centers (RR 1.180, p<0.0001) were associated with higher likelihood of CLND. Regional differences in likelihood of CLND were also present (p<0.0001). Conclusions: CLND in SNPM decreased over time, with the greatest change in 2016. Several patient, pathologic, and institutional characteristics were associated with likelihood of CLND. As evidence supports close observation for selected patients, efforts should be undertaken to improve and standardize patient selection for CLND across institutions caring for patients with melanoma.
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3 Abbreviations: Sentinel lymph node biopsy: SLNB Sentinel node positive melanoma: SNPM Completion lymph node dissection: CLND National Cancer Center Network: NCCN Multi-Center Selective Lymphadenectomy Trial II: MSLT-II Commission on Cancer: CoC National Cancer Database: NCDB High-volume centers: HVCs Non-high volume centers: nHVCs International Classification of Disease for Oncology: ICD-O American Joint Commission on Cancer: AJCC National Comprehensive Cancer Network: NCCN
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Introduction: A sentinel lymph node biopsy (SLNB) in melanoma provides critical prognostic and staging information in patients with clinically node negative tumors and is recommended for patients with melanoma of a depth ≥1.0mm (1–5). Until recently, the standard of care for most patients with sentinel-node positive melanoma (SNPM) was completion lymph node dissection (CLND)(3, 6). This was considered therapeutic, and was used as a marker of quality in the surgical care of melanoma (7–9). However, the therapeutic benefit of CLND has been questioned, particularly for patients with low volume sentinel-node disease burden (10–19). In recent years, two randomized controlled trials have examined this question. The first of these, DeCOG-SLT, presented in 2015 (20) and published in 2016 (21) included 483 patients with SNPM. There was no difference in distant melanoma-free survival amongst patients who did and did not undergo CLND (21). This finding was durable in long-term follow up (22). The Multi-Center Selective Lymphadenectomy Trial II (MSLT-II) (23) evaluated the utility of CLND in 1939 patients with intermediate-thickness melanoma with a positive SLN who were randomized to observation or immediate CLND. In 2017, this trial similarly failed to show a difference in melanoma specific survival in patients undergoing immediate CLND. As such, it appears safe to observe many patients with SNPM, and this approach has been incorporated into current NCCN guidelines (5). As the first of these trials were initially reported in 2015, this study aims to evaluate practice patterns of CLND in the immediate time period before and after they became available in an effort to determine how quickly this data was translated into clinical practice and examine associated measures predictive of CLND. We hypothesize that utilization of CLND decreased rapidly over time in response to these results.
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5 Methods: The study utilized the National Cancer Database (NCDB), a national hospital-based cancer registry jointly sponsored by the American Cancer Society and American College of Surgeons that is sourced from approximately 1,500 Commission on Cancer (CoC)-accredited facilities (24). It provides diagnostic, staging, treatment and outcomes information. In a recent analysis this database was estimated to capture 72% of all incident cancer cases in the United States, and 52% of incident melanoma cases (25). The 2016 NCDB Participant User File was queried for all patients ≥18 years diagnosed with melanoma (based on World Health Organization’s International Classification of Disease for Oncology (ICD-0), 3rd edition) 20122016 (the most recent year available). We further narrowed our cohort to patients who had a sentinel lymph node biopsy (SLNB) or SLNB plus complete lymph node dissection (CLND) (whether concurrently or as a separate procedure) using the “Scope of Regional Lymph Node Surgery 2012” variable. This variable, which provides detailed coding on the type and timing of lymph node surgery, is only available in this format for cases diagnosed after January 1, 2012 (26). We defined our two comparative cohorts as those who had SLNB only and those who had SLNB plus CLND. Additional inclusion criteria were as follows: first and only cancer, at least 1 regional node examined, and node positive disease (defined as at least one of the following: American Joint Commission on Cancer (AJCC) pathologic stage III disease, AJCC pathologic N staging listed as 1, 2 or 3, or having ≥1 regional node(s) positive). We excluded patients with clinically positive lymph nodes (AJCC clinical N >0), with metastatic disease, with no tumor size data, with no regional nodes examined, with unknown or negative regional lymph nodes, and patients treated with palliative intent or who died within 90 days.
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6 Patient demographic (age, sex, race/ethnicity), socioeconomic (area-based education, area-based income, insurance status), geographic (rural/urban status, travel distance), clinical (Charlson-Deyo score, tumor location) and tumor pathologic (Breslow thickness, lymphovascular invasion, ulceration, mitoses) measures were analyzed. Tumor volume in positive sentinel lymph nodes is not captured by the NCDB and therefore is not included in the analysis. Facility factors (facility region, facility type, hospital melanoma volume) were also examined. For hospital volume, we first calculated the average yearly facility volume using the number of SLNBs performed at each facility over the entire study period divided by five (number of years in the study period). We then defined hospital volume quintiles based on the average yearly facility volume, with the 80th percentile as our high volume cutpoint (≥15 SLNBs per year in this cohort). A facility performing at this level or above for an individual year was considered high volume for that year. The cutpoint was held constant from year to year and facilities could change groups over time. Chi-squared tests were used to examine differences in frequencies of categorical variables, and T-tests were used to examine differences in continuous variables. Poisson regression was used to assess temporal trends in the use of CLND and to assess the relative risks of patient, clinical, and institutional factors associated with the use of CLND in patients with SNPM. Cases with missing data were excluded from the regression analysis. Time trends in the use of CLND between high-volume centers (HVCs) and non-high volume centers (nHVCs) were also examined. This study was deemed exempt by the University of North Carolina Institutional Review Board. All analyses were done in SAS Enterprise Guide, version 7.11 (Cary, NC). P-values were considered significant at <0.05. The American College of Surgeons and the Commission on
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7 Cancer have not verified and are not responsible for the analytic or statistical methodology used, or the conclusions drawn from these data by the investigators. Results: From 2012-2016, 7,146 patients were identified with SNPM. Of these patients, 3,002 (42%) underwent SLNB only and 4,144 (58%) patients underwent SLNB plus CLND (Table 1). The average age overall was 57 years (SD: 15.9) and the cohort was predominantly white males (97% white, 59% males). Most patients had a Charlson-Deyo score of 0 (83%), had private insurance (56%), were from an urban location (95%), and went to HVCs (71%). Additional patient and facility characteristics are shown in Table 1. Tumor specific variables are summarized overall and by treatment group in Table 2. Most tumors had a Breslow thickness <4mm (72%) and the most common site was the trunk (38%). Ulceration and lymphovascular invasion were seen in 43% and 15% of cases, respectively. In univariate analysis, the two treatment groups significantly differed by many patient demographic, clinicopathologic, and facility factors (sex, payer, education, Charlson-Deyo score, year of diagnosis, facility region, facility type, facility volume, Breslow thickness, ulceration, primary tumor mitotic count, and primary site. (Tables 1&2). Overall observed trends in the number of CLNDs over time are shown in Figure 1. The total number of SNPM patients increased every year from 1,241 patients in 2012 to 1,703 in 2016. The proportion of SNPM patients undergoing CLND decreased over time from 63% in 2012 to 50% in 2016 (p<0.0001). The largest decrease occurred from 2015 to 2016 (-7%; 57% to 50%, respectively) and was greater than the decrease over the 4 prior years combined (-6%; 63% to 57%). Figure 2 shows trends in number of CLNDs over time stratified by HVC (Figure 2a) and non-HVC (Figure 2b). Overall, rates of CLND were higher in HVC (61%) as compared to
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8 non-HVC (50%) (not shown in figure). The proportion of CLNDs decreased over time for both HVC (66.6% to 52.2%, p<0.0001) and non-HVC (54.6% to 50.3%, p=0.0597), but at greater magnitude in HVC (Figure 2). Table 3 shows results of the Poisson regression model with estimated relative risks of CLNB for several patient, facility, and pathologic factors. Factors that decreased likelihood of CLND were year of diagnosis (RR in 2016 vs 2012: .802; 95% CI: 0.742,0.865; overall p<0.0001) and increasing age (RR: 0.988; 95% CI: 0.985,0.99; p=0.0007). Factors that significantly increased the likelihood of CLND were ulceration (RR: 1.066; 95% CI: 1.012,1.122, p=0.02), increasing Breslow depth (RR:1.015; 95% CI: 1.004,1.025; p=0.006), anatomic location anywhere but lower extremity (RR: 1.28-1.31; p<0.0001) and treatment at HVCs (RR: 1.18; 95% CI: 1.099, 1.266; p<0.0001). Facility region (overall p<0.0001) was associated with CLND but rural/urban status and travel distance were not. Discussion: Recently reported randomized controlled trials have demonstrated that patients with SNPM may be able to forgo CLND and undergo observation alone with no detrimental effect on overall or melanoma specific survival (21–23). Our analysis shows that patients with SNPM captured in the NCDB are increasingly likely to have CLND omitted as part of their care, a trend that accelerated in 2015, the first year prospective randomized data were reported, and continued in 2016. We found that the proportion of patients with SNPM undergoing CLND decreased over time from 63% to 50% from 2012 to 2016, with the largest change from 2015-2016, a magnitude which was larger than the difference between all other years combined. Our study is similar to the recent analysis by Hewitt and colleagues, which examined data from years prior to release of the RCT results (27). Our cohort of patients was slightly different
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9 as our study excluded patients with a prior cancer, those who died within 90 days, and those treated with palliative intent. Despite these differences, the overall rate of CLND utilization was similar between their study and ours (57.0% vs 58%, respectively). We also find increases in the total number of patients with SNPM over time. The treatment of advanced melanoma requires a multi-modal and multi-disciplinary approach (5), and treatment at HVCs is associated with improved survival in melanoma (28, 29). Thus, the trend in our data may be reflective of increasing referral from community settings and non-CoC facilities (not captured by the NCDB) to more specialized centers over time. This is supported by data demonstrating the increase in SNPM volume over time was primarily in HVCs compared to non-HVCs (Figure 2). We additionally examined factors associated with CLND. Similar to other analyses, we find that older age is associated with a lower likelihood of undergoing CLND (7, 11, 27, 30, 31). This may be due to both patient refusals to undergo the procedure and surgeons advising against a potentially morbid operation in an elderly patient (32). We also find no association of sex and likelihood of CLND, consistent with other data (11, 27, 32). Tumor location, especially in the lower extremity, is often associated with lower likelihood of CLND in SNPM, likely due to the increased morbidity of the procedure (7, 27, 31, 32), and we find similar results. This effect did not significantly change over time. Other tumor pathologic factors associated with CLND were Breslow depth and ulceration. There are multiple studies examining clinicopathologic factors associated with nonsentinel node positivity on CLND, and a 2013 meta-analysis showed that tumor ulceration was associated with a significantly higher odds of additional non-SLN positivity while Breslow depth was found to be equivocal (16). Other studies have found Breslow depth to predict additional
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10 non-SLN positivity (10, 33). Multi-variate analysis from MSLT-II showed Breslow depth and ulceration were associated with worse melanoma specific survival for both the observation and the CLND arms (23). Previous studies have shown that thicker primary tumors and those with ulceration have an increased risk of hematogenous metastasis (34), thus the prognostic significance of these factors is likely independent of their effect on additional regional node burden. Prior studies have examined the association of facility melanoma volume on CLND in SNPM with conflicting results (7, 27). Using NCDB data from 2004-2005, Bilimoria et al found that patients treated at lower volume facilities had lower odds of CLND in SNPM, while Hewitt et al found no effect of hospital volume using NCDB data from 2012-2015. These studies both used total melanoma case volume while our study used the number of melanoma sentinel node procedures to define HVCs. By using the number of SLNBs to define hospital volume rather than total surgical case volume, this may be more sensitive to the association of hospital volume on regional node procedures. We found hospitals performing >15 SLNBs per year were more likely to utilize CLND. HVCs may be more likely to utilize CLND if they are referred more advanced cases with heavier regional node burden, but it is difficult to assess this hypothesis without data on the sentinel node tumor burden. Utilization in both HVCs and non-HVCs decreased over time, a magnitude that was greater in HVCs. This may reflect a more rapid incorporation of the randomized trial data into clinical practice in high volume, academic centers. Geographic and regional variations in treatment patterns are prevalent in melanoma, as well as multiple other cancers (35–37). Cormier and colleagues (11), in an analysis of SEER data from 1998-2001, found that the odds of guideline concordant management in melanoma overall
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11 and by stage varied significantly by SEER registry. Using the NCDB, we found an overall effect of census region in the use of CLND. The explanation for this is likely complex and may be partly due to differences in underlying patient and physician/health system factors (38, 39), and is worth further study in melanoma specifically to determine barriers to treatment standardization and the diffusion of clinical trial data into surgical practice. The study has several limitations. Most importantly, as Hewitt and colleagues (27) have noted, it is difficult to determine from NCDB data (even after updating the sentinel node procedure coding in 2012) exactly who should undergo CLND in SNPM, as there is no variable that defines the size or volume of sentinel node disease burden. This is important to consider since both the DeCOG-SLT and MSLT-II trials included significant proportions of patients with very small tumor burden in the sentinel node. In both studies, 66% of patients had a SLN metastasis no larger than 1mm in size, a finding that should be taken into account when considering optimal management for individual patients with SNPM. Without the sentinel node data, we cannot determine whether the appropriate patients are being offered observation and/or if trial results are being overextended to patients with a larger sentinel node burden. Other limitations include the fact that NCDB is a hospital-based cohort rather than a population-based sample. As a result, we cannot account for practice patterns in facilities that are not CoC accredited. Additionally, we cannot account for time trends in CLND prior to 2012 as the needed data were not available before that time. Lastly, there were 1,064 cases with missing data for both facility type and facility region, which could affect the findings of regional variation in practice patterns. Conclusion:
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12 We found declining rates of CLND in SNPM which increased in 2016, corresponding to initial reports of prospective, randomized data suggesting limited benefit to CLND. Several patient, clinical, and pathologic characteristics were associated with the likelihood of CLND, and there is regional variation in practice patterns, although regardless of practice setting, procedural volume was most associated with change in practice pattern. While this demonstrates early dissemination of clinical trials data, it is likely that greater change will be seen beginning in 2017/2018, reflecting reporting of the MSLT-II trial. Regardless, it will be important to continue to disseminate this information and standardize the patient cohort who are offered observation versus CLND, as it is likely that there remains a population of patients with SLN positive melanoma who still benefit from CLND.
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13 References: 1. Van Der Ploeg APT, Haydu LE, Spillane AJ, et al. Outcome following sentinel node biopsy plus wide local excision versus wide local excision only for primary cutaneous melanoma: Analysis of 5840 patients treated at a single institution. Ann Surg 2014;260:149–157. 2. Morton D, Thompson JF, Cochran A, et al. Sentinel-Node Biopsy or Nodal Observation in Melanoma. N Engl J Med 2006;355:1307–1317. 3. Morton DL, Thompson JF, Cochran AJ, et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med 2014;370:599–609. 4. Wong SL, Balch CM, Hurley P, et al. Sentinel lymph node biopsy for melanoma: American society of clinical oncology and society of surgical oncology joint clinical practice guideline. Ann Surg Oncol 2012;19:3313–3324. 5. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Cutaneous Melanoma 2019. Available at: https://www.nccn.org/professionals/physician_gls/pdf/cutaneous_melanoma_blocks.pdf. Accessed September 30, 2019. 6. National Comprehensive Cancer Network. Clinical Practce Guidelines in Oncology: Cutaneous Melanoma 2016. Available at: https://www2.trikobe.org/nccn/guideline/skin/english/skin_melanoma.pdf. Accessed September 30, 2019. 7. Bilimoria KY, Balch CM, Bentrem DJ, et al. Complete lymph node dissection for sentinel node-positive melanoma: Assessment of practice patterns in the United States. Ann Surg Oncol 2008;15:1566–1576. 8. Bilimoria KY, Raval M V., Bentrem DJ, et al. National assessment of melanoma care using formally developed quality indicators. J Clin Oncol 2009;27:5445–5451.
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14 9. Minami CA, Wayne JD, Yang AD, et al. National Evaluation of Hospital Performance on the New Commission on Cancer Melanoma Quality Measures. Ann Surg Oncol 2016;23:3548–3557. 10. Cochran AJ, Wen DR, Huang RR, et al. Prediction of metastatic melanoma in nonsentinel nodes and clinical outcome based on the primary melanoma and the sentinel node. Mod Pathol 2004;17:747–755. 11. Cormier JN, Xing Y, Ding M, et al. Population-based assessment of surgical treatment trends for patients with melanoma in the era of sentinel lymph node biopsy. J Clin Oncol 2005;23:6054–6062. 12. Dewar DJ, Newell B, Green MA, et al. The microanatomic location of metastatic melanoma in sentinel lymph nodes predicts nonsentinel lymph node involvement. J Clin Oncol 2004;22:3345–3349. 13. Fink AM, Weihsengruber F, Duschek N, et al. Value of micromorphometric criteria of sentinel lymph node metastases in predicting further nonsentinel lymph node metastases in patients with melanoma. Melanoma Res 2011;21:139–143. 14. van Akkooi ACJ, de Wilt JHW, Verhoef C, et al. Clinical relevance of melanoma micrometastases (<0.1 mm) in sentinel nodes: Are these nodes to be considered negative? Ann Oncol 2006;17:1578–1585. 15. van Akkooi ACJ, de Wilt JHW, Verhoef C, Eggermont AMM. Isolated tumor cells and longterm prognosis of patients with melanoma. Ann Surg Oncol 2008;15:1547–1548. 16. Nagaraja V, Eslick GD. Is complete lymph node dissection after a positive sentinel lymph node biopsy for cutaneous melanoma always necessary? A meta-analysis. Eur J Surg Oncol 2013;39:669–680. 17. Namikawa K, Yamazaki N, Nakai Y, et al. Prediction of additional lymph node positivity
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15 and clinical outcome of micrometastases in sentinel lymph nodes in cutaneous melanoma: A multi-institutional study of 450 patients in Japan. J Dermatol 2012;39:130–137. 18. Van Der Ploeg IMC, Kroon BBR, Antonini N, et al. Is completion lymph node dissection needed in case of minimal melanoma metastasis in the sentinel node? Ann Surg 2009;249:1003– 1007. 19. Ollila DW, Ashburn JH, Amos KD, et al. Metastatic Melanoma Cells in the Sentinel Node Cannot Be Ignored. J Am Coll Surg 2009;208:924–929. 20. Leiter U, Stadler R, Mauch C, et al. Survival of SLNB-positive melanoma patients with and without complete lymph node dissection: A multicenter, randomized DECOG trial. J Clin Oncol 2015;33:LBA9002. 21. Leiter U, Stadler R, Mauch C, et al. Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): a multicentre, randomised, phase 3 trial. Lancet Oncol 2016;17:757–67. 22. Leiter U, Stadler R, Mauch C, et al. Final Analysis of DeCOG-SLT Trial: No Survival Benefit for Complete Lymph Node Dissection in Patients With Melanoma With Positive Sentinel Node. J Clin Oncol 2019;37:3000–3009. 23. Faries MB, Thompson JF, Cochran AJ, et al. Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma. N Engl J Med 2017;376:2211–2222. 24. National Cancer Database. American College of Surgeons Cancer Programs. 2019. Chicago, Illinois. Available at: https://www.facs.org/quality-programs/cancer/ncdb. Accessed September 30, 2019. 25. Mallin K, Browner A, Palis B, et al. Incident Cases Captured in the National Cancer Database Compared with Those in U.S. Population Based Central Cancer Registries in 2012–
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16 2014. Ann Surg Oncol 2019;26:1604–1612. 26. Commission on Cancer. Scope of Regional Lymph Node Surgery: A Review of Data Validity, Revised Coding Directives, and Agency Transition Plans. 2012. Available at: https://www.facs.org/~/media/files/quality%20programs/cancer/ncdb/scope%20regional%20lym ph%20node%20surgery.ashx. Accessed September 30, 2019. 27. Hewitt DB, Merkow RP, DeLancey JO, et al. National practice patterns of completion lymph node dissection for sentinel node-positive melanoma. J Surg Oncol 2018;118:493–500. 28. Huo J, Lairson DR, Du XL, et al. Hospital Case Volume Is Associated with Improved Survival for Patients with Metastatic Melanoma. Am J Clin Oncol Cancer Clin Trials 2016;39:491–496. 29. Cheraghlou S, Agogo GO, Girardi M. Treatment of primary nonmetastatic melanoma at high-volume academic facilities is associated with improved long-term patient survival. J Am Acad Dermatol 2019;80:979–989. 30. Kingham T, Panageas KS, Ariyan CE, et al. Outcome of Patients with a Positive Sentinel Lymph Node who do not Undergo Completion Lymphadenectomy. Ann Surg Oncol 2010;17:514–520. 31. Chu BS, Koffi W, Hoehn RS, et al. Improvement and persistent disparities in completion lymph node dissection: Lessons from the National Cancer Database. J Surg Oncol 2017;116:1176–1184. 32. Shah DR, Yang AD, Maverakis E, Martinez SR. Age-related disparities in use of completion lymphadenectomy for melanoma sentinel lymph node metastasis. J Surg Res 2013;185:240–244. 33. Schuitevoerder D, Bubic I, Fortino J, et al. Patients with sentinel lymph node positive melanoma: Who needs completion lymph node dissection? Am J Surg 2018;215:868-872.
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17 34. Faut M, Wevers KP, van Ginkel RJ, et al. Nodular Histologic Subtype and Ulceration are Tumor Factors Associated with High Risk of Recurrence in Sentinel Node-Negative Melanoma Patients. Ann Surg Oncol 2017;24:142–149. 35. Nattinger AB, Gottlieb MS, Veum J, et al. Geographic Variation in the Use of BreastConserving Treatment for Breast Cancer. N Engl J Med 1992;326. 36. Kasumova GG, Eskander MF, de Geus SWL, et al. Regional variation in the treatment of pancreatic adenocarcinoma: Decreasing disparities with multimodality therapy. Surgery 2017;162:275–284. 37. Sineshaw HM, Wu XC, Dana Flanders W, et al. Variations in receipt of curative-intent surgery for early-stage non-small cell lung cancer (NSCLC) by state. J Thorac Oncol 2016;11:880–889. 38. Wennberg JE, Fisher ES, Skinner JS. Geography and the debate over medicare reform. Health Aff 2003;22. 39. Keating NL, Landrum MB, Lamont EB, et al. Area-Level Variations in Cancer Care and Outcomes. Medical Care 2012;50:366–373.
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Table 1. Demographic, Clinical, and Facility Characteristics
Variable Sex, n (%) Male Female Race, n (%) White Black Other Missing Spanish/Hispanic origin, n (%) Non-Spanish; non-Hispanic Hispanic Unknown Age, y, mean (SD) Charlson-Deyo score, n (%) 0 1 2 3+ Primary payor, n (%) Not insured Private insurance/managed care Medicaid Medicare Other government Insurance status unknown Median income 2012-2016, n (%) Missing/unknown <$40,227 $40,227-$50,353 $50,354-$63,332 ≥$63,333 Percent no high school degree 20122016, n (%) Missing/unknown ≥17.6%
All (n=7,146)
SLNB Only (n= 3,002)
SLNB+CLND (n=4,144)
4192(59) 2954(41)
1691(56) 1311(44)
2501(60) 1643(40)
6926(97) 70(1) 63(1) 87(1)
2902(97) 35(1) 22(1) 43(1)
4024(97) 35(1) 41(1) 44(1)
p Value 0.0007
0.1624
0.8448 6788(95) 214(3) 144(2) 57.2 (15.9)
2848(95) 94(3) 60(2) 60.2 (16.2)
3940(95) 120(3) 84(2) 55.1 (15.3)
5915(83) 952(13) 184(3) 95(1)
2442(81) 419(14) 97(3) 44(1)
3473(84) 533(13) 87(2) 51(1)
0.0004 0.0066
<.0001 246(3) 3992(56) 394(6) 2322(32) 98(1) 94(1)
94(3) 1504(50) 144(5) 1181(39) 38(1) 41(1)
152(4) 2488(60) 250(6) 1141(28) 60(1) 53(1) 0.0626
90(1) 951(13) 1505(21) 1806(25) 2794(39)
38(1) 403(13) 626(21) 716(24) 1219(41)
52(1) 548(13) 879(21) 1090(26) 1575(38)
83(1) 947(13)
34(1) 440(15)
49(1) 507(12)
0.0072
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19 10.9%-17.5% 1767(25) 703(23) 1064(26) 6.3%-10.8% 2219(31) 917(31) 1302(31) <6.3% 2130(30) 908(30) 1222(29) Urban/rural, n (%) Missing/unknown 183(3) 74(2) 109(3) Rural 142(2) 69(2) 73(2) Urban 6821(95) 2859(95) 3962(96) Travel distance, miles, median (IQR) 16.9 (7.6, 40.6) 15.0 (6.7, 35.2) 18.5 (8.2, 45.6) Year of diagnosis, n (%) 2012 1241(17) 461(15) 780(19) 2013 1337(19) 527(18) 810(20) 2014 1416(20) 543(18) 873(21) 2015 1449(20) 623(21) 826(20) 2016 1703(24) 848(28) 855(21) Facility location, n (%) Missing/unknown 1062(15) 364(12) 698(17) New England 329(5) 134(4) 195(5) Middle Atlantic 991(14) 476(16) 515(12) South Atlantic 1189(17) 547(18) 642(15) East North Central 1243(17) 463(15) 780(19) East South Central 390(5) 193(6) 197(5) West North Central 548(8) 212(7) 336(8) West South Central 354(5) 166(6) 188(5) Mountain 410(6) 146(5) 264(6) Pacific 630(9) 301(10) 329(8) Facility type Missing/unknown 1062(15) 364(12) 698(17) Community cancer program 333(5) 173(6) 160(4) Comprehensive community cancer program 1736(24) 821(27) 915(22) Academic/research program 3326(47) 1312(44) 2014(49) Integrated network cancer program 689(10) 332(11) 357(9) Facility volume Non-high-volume center (<15 sentinel node procedures/year) 2077(29) 1033(34) 1044(25) High-volume center (≥15 sentinel node procedures/year) 5069(71) 1969(66) 3100(75) SLNB, sentinel lymph node biopsy; SLNB+CLND, sentinel lymph node biopsy and completion lymph node dissection
19
0.1107
<.0001
<.0001
<.0001
<.0001
20
Table 2. Tumor Characteristics All (n=7,146)
SNLB (n= 3,002)
SNLB+CLND (n=4,144)
Characteristic Primary Site, n(%) Head and Neck 992(14) 394(13) 598(14) Skin of trunk 2720(38) 980(33) 1740(42) Skin of upper limb and shoulder 1563(22) 636(21) 927(22) Skin of lower limb and hip 1819(25) 971(32) 848(20) Unspecified 52(1) 21(1) 31(1) Breslow Thickness, n(%) .1 mm to 1 mm 907(13) 422(14) 485(12) 1.1 mm to 2 mm 2002(28) 856(29) 1146(28) 2.1 mm to 4 mm 2198(31) 886(30) 1312(32) ≥ 4.1 mm 1890(26) 763(25) 1127(27) Microinvasion, not documented, or unknown 149(2) 75(2) 74(2) Ulceration, n(%) No ulceration present 4062(57) 1753(58) 2309(56) Ulceration present 3084(43) 1249(42) 1835(44) Vascular Invasion Missing/Unknown 1130(16) 509(17) 621(15) Not present 4944(69) 2036(68) 2908(70) Present 1072(15) 457(15) 615(15) Primary Tumor Mitotic Count, n(%) 0 mitoses per square mm 488(7) 229(8) 259(6) 1 to 2 mitoses per square mm 2147(30) 894(30) 1253(30) 3 to 4 mitoses per square mm 1245(17) 539(18) 706(17) 5+ mitoses per square mm 2680(38) 1054(35) 1626(39) Missing 586(8) 286(10) 300(7) SLNB, sentinel lymph node biopsy; SLNB+CLND, sentinel lymph node biopsy and
p Value <.0001
0.0019
0.0242
0.3825
<.0001
completion lymph node dissection
20
21
Table 3. Poisson Model Evaluating Factors Associated with Sentinel Lymph Node Biopsy and Completion Dissection vs Sentinel Lymph Node Biopsy Only
Variable, N=4815* Year of diagnosis 2013 2014 2015 2016 2012 Race American Indian/Alaska Native Asian/Pacific Islander Black White Sex Female Male Age, y Insurance Not insured Public insurance Private insurance/managed care Urban/rural Rural Urban Distance to facility (10-mile increments) Charlson-Deyo Score 1 2 3+ 0 Ulceration Yes No Lymphovascular invasion Present Not present Breslow depth (in mm) Facility type Community cancer program
Relative risk
95% CI
1.005 0.970 0.896 0.801 Reference
0.936,1.08 0.902,1.043 0.831,0.966 0.742,0.865
1.206 0.981 0.861 Reference
0.829,1.753 0.748,1.286 0.632,1.171
Overall p value <.0001
0.6034
0.211 0.968 Reference 0.988
0.921,1.019
0.907 0.970 Reference
0.792,1.038 0.912,1.031
0.985,0.99
<.0001 0.24
0.777 0.977 Reference
0.83,1.15
1.001
0.999,1.003
1.038 0.911 1.128 Reference
0.969,1.112 0.768,1.081 0.924,1.376
0.3775 0.2906
0.0154 1.066 Reference
1.012,1.122 0.2761
0.965 Reference 1.015
0.905,1.03 1.004,1.025
1.050
0.983,1.122
0.0058 0.1409
21
22 Academic/research program Integrated network cancer program Comprehensive community cancer program Facility region East North Central East South Central Middle Atlantic Mountain New England Pacific South Atlantic West North Central West South Central Facility volume ≥15 SLNBs per year <15 SLNBs per year Primary site Head and neck Skin of trunk Skin of upper limb and shoulder Unspecified Skin of lower limb and hip
0.942
0.82,1.083
0.968
0.88,1.064
Reference <.0001 1.109 0.910 0.909 1.124 1.047 0.971 0.967 1.091 Reference
0.977,1.259 0.778,1.065 0.793,1.041 0.976,1.294 0.896,1.223 0.841,1.12 0.849,1.101 0.953,1.25
1.180 Reference
1.099,1.266
<.0001
<.0001 1.278 1.314 1.300 1.400 Reference
1.17,1.395 1.225,1.408 1.204,1.403 0.966,2.029
*Patients with complete data included in regression analysis
22
23 Figure legend Figure 1. Overall time trends in surgical management of sentinel node positive melanoma. completion lymph node dissection use decreased over time, with the largest decrease from 20152016. Overall p-value for trend: <0.0001 Figure 2. Trends in surgical management of sentinel node positive melanoma over time in (A) high-volume centers and (B) low-volume centers. High-volume centers had a higher proportion of patients undergoing completion lymph node dissection (CLND) but had a larger decrease over the study period (overall p value for trend <0.001). Low-volume centers had a smaller proportion undergoing completion lymph node dissection CLND, but had a non-significant, smaller downward trend in CLND use (overall p value for trend p=0.06). SNPM, sentinel node positive melanoma
23
24 Precis Randomized trials have shown limited value of completion lymph node dissection in select patients with sentinel node positive melanoma. In an assessment of national practice patterns using the National Cancer Database, we identify significant declines in the use of completion lymph node dissection beginning shortly after randomized trial data was initially reported.
24
S1072-7515(20)30071-5
DOI:
https://doi.org/10.1016/j.jamcollsurg.2019.12.010
Reference:
ACS 9703
To appear in:
Journal of the American College of Surgeons
Received Date: 16 December 2019 Accepted Date: 16 December 2019
Please cite this article as: Herb JN, Dunham LN, Ollila DW, Stitzenberg KB, Meyers MO, Use of Completion Lymph Node Dissection for Sentinel Lymph Node Positive Melanoma, Journal of the American College of Surgeons (2020), doi: https://doi.org/10.1016/j.jamcollsurg.2019.12.010. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 by the American College of Surgeons. Published by Elsevier Inc. All rights reserved.
1 Use of Completion Lymph Node Dissection for Sentinel Lymph Node Positive Melanoma Joshua N Herb, MDa, Lisette N Dunham, MSPHb, David W Ollila, MD, FACSa,b, Karyn B Stitzenberg, MD, MPH, FACSa,b, Michael O Meyers, MD, FACSa,b a
Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC b
Disclosure Information: Nothing to disclose. Support: Dr Herb is supported by a National Service Research Award Pre-Doctoral/PostDoctoral Traineeship from the Agency for Healthcare Research and Quality sponsored by the Cecil G Sheps Center for Health Services Research, University of North Carolina at Chapel Hill, Grant No. 5T32 HS000032. Presented at the 131st Annual Meeting of the Southern Surgical Association, Hot Springs, VA, December 2019 Corresponding Author Information: Joshua Herb, MD Division of Surgical Oncology, CB#7213 UNC Department of Surgery Chapel Hill, NC, 27599 Email: [email protected] Brief Title: Lymph Node Dissection in Melanoma
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Background: For patients with sentinel node positive melanoma (SNPM), randomized trials, first reported in 2015, show no benefit for routine completion lymph node dissection (CLND) in selected patients. This study examines time trends in CLND and explores institutional and clinical factors associated with CLND. Study Design: The National Cancer Database was queried for patients > 18 years old from 20122016 with SNPM. A high-volume center was defined as >80th percentile for number of sentinel node procedures. Poisson regression assessed temporal trends, and identified patient, pathologic, and institutional characteristics associated with CLND. Results: From 2012-2016, 7146 patients with SNPM were identified. The proportion of patients undergoing CLND was steady in years 2012-2014 (61-63%), but decreased to 57% in 2015 and 50% in 2016 (p<0.0001). The proportion of patients with SNPM who underwent CLND decreased over time for both high (66% to 52%, p<0.0001) and lower volume centers (55% to 45%, p=0.06). Female sex (RR 0.97, p<0.001) and increasing age (RR 0.98, p<0.0001) were associated with lower likelihood of CLND. Increased Breslow depth (RR 1.015, p=0.006), ulceration (RR 1.067, p=.02), and high-volume centers (RR 1.180, p<0.0001) were associated with higher likelihood of CLND. Regional differences in likelihood of CLND were also present (p<0.0001). Conclusions: CLND in SNPM decreased over time, with the greatest change in 2016. Several patient, pathologic, and institutional characteristics were associated with likelihood of CLND. As evidence supports close observation for selected patients, efforts should be undertaken to improve and standardize patient selection for CLND across institutions caring for patients with melanoma.
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3 Abbreviations: Sentinel lymph node biopsy: SLNB Sentinel node positive melanoma: SNPM Completion lymph node dissection: CLND National Cancer Center Network: NCCN Multi-Center Selective Lymphadenectomy Trial II: MSLT-II Commission on Cancer: CoC National Cancer Database: NCDB High-volume centers: HVCs Non-high volume centers: nHVCs International Classification of Disease for Oncology: ICD-O American Joint Commission on Cancer: AJCC National Comprehensive Cancer Network: NCCN
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Introduction: A sentinel lymph node biopsy (SLNB) in melanoma provides critical prognostic and staging information in patients with clinically node negative tumors and is recommended for patients with melanoma of a depth ≥1.0mm (1–5). Until recently, the standard of care for most patients with sentinel-node positive melanoma (SNPM) was completion lymph node dissection (CLND)(3, 6). This was considered therapeutic, and was used as a marker of quality in the surgical care of melanoma (7–9). However, the therapeutic benefit of CLND has been questioned, particularly for patients with low volume sentinel-node disease burden (10–19). In recent years, two randomized controlled trials have examined this question. The first of these, DeCOG-SLT, presented in 2015 (20) and published in 2016 (21) included 483 patients with SNPM. There was no difference in distant melanoma-free survival amongst patients who did and did not undergo CLND (21). This finding was durable in long-term follow up (22). The Multi-Center Selective Lymphadenectomy Trial II (MSLT-II) (23) evaluated the utility of CLND in 1939 patients with intermediate-thickness melanoma with a positive SLN who were randomized to observation or immediate CLND. In 2017, this trial similarly failed to show a difference in melanoma specific survival in patients undergoing immediate CLND. As such, it appears safe to observe many patients with SNPM, and this approach has been incorporated into current NCCN guidelines (5). As the first of these trials were initially reported in 2015, this study aims to evaluate practice patterns of CLND in the immediate time period before and after they became available in an effort to determine how quickly this data was translated into clinical practice and examine associated measures predictive of CLND. We hypothesize that utilization of CLND decreased rapidly over time in response to these results.
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5 Methods: The study utilized the National Cancer Database (NCDB), a national hospital-based cancer registry jointly sponsored by the American Cancer Society and American College of Surgeons that is sourced from approximately 1,500 Commission on Cancer (CoC)-accredited facilities (24). It provides diagnostic, staging, treatment and outcomes information. In a recent analysis this database was estimated to capture 72% of all incident cancer cases in the United States, and 52% of incident melanoma cases (25). The 2016 NCDB Participant User File was queried for all patients ≥18 years diagnosed with melanoma (based on World Health Organization’s International Classification of Disease for Oncology (ICD-0), 3rd edition) 20122016 (the most recent year available). We further narrowed our cohort to patients who had a sentinel lymph node biopsy (SLNB) or SLNB plus complete lymph node dissection (CLND) (whether concurrently or as a separate procedure) using the “Scope of Regional Lymph Node Surgery 2012” variable. This variable, which provides detailed coding on the type and timing of lymph node surgery, is only available in this format for cases diagnosed after January 1, 2012 (26). We defined our two comparative cohorts as those who had SLNB only and those who had SLNB plus CLND. Additional inclusion criteria were as follows: first and only cancer, at least 1 regional node examined, and node positive disease (defined as at least one of the following: American Joint Commission on Cancer (AJCC) pathologic stage III disease, AJCC pathologic N staging listed as 1, 2 or 3, or having ≥1 regional node(s) positive). We excluded patients with clinically positive lymph nodes (AJCC clinical N >0), with metastatic disease, with no tumor size data, with no regional nodes examined, with unknown or negative regional lymph nodes, and patients treated with palliative intent or who died within 90 days.
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6 Patient demographic (age, sex, race/ethnicity), socioeconomic (area-based education, area-based income, insurance status), geographic (rural/urban status, travel distance), clinical (Charlson-Deyo score, tumor location) and tumor pathologic (Breslow thickness, lymphovascular invasion, ulceration, mitoses) measures were analyzed. Tumor volume in positive sentinel lymph nodes is not captured by the NCDB and therefore is not included in the analysis. Facility factors (facility region, facility type, hospital melanoma volume) were also examined. For hospital volume, we first calculated the average yearly facility volume using the number of SLNBs performed at each facility over the entire study period divided by five (number of years in the study period). We then defined hospital volume quintiles based on the average yearly facility volume, with the 80th percentile as our high volume cutpoint (≥15 SLNBs per year in this cohort). A facility performing at this level or above for an individual year was considered high volume for that year. The cutpoint was held constant from year to year and facilities could change groups over time. Chi-squared tests were used to examine differences in frequencies of categorical variables, and T-tests were used to examine differences in continuous variables. Poisson regression was used to assess temporal trends in the use of CLND and to assess the relative risks of patient, clinical, and institutional factors associated with the use of CLND in patients with SNPM. Cases with missing data were excluded from the regression analysis. Time trends in the use of CLND between high-volume centers (HVCs) and non-high volume centers (nHVCs) were also examined. This study was deemed exempt by the University of North Carolina Institutional Review Board. All analyses were done in SAS Enterprise Guide, version 7.11 (Cary, NC). P-values were considered significant at <0.05. The American College of Surgeons and the Commission on
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7 Cancer have not verified and are not responsible for the analytic or statistical methodology used, or the conclusions drawn from these data by the investigators. Results: From 2012-2016, 7,146 patients were identified with SNPM. Of these patients, 3,002 (42%) underwent SLNB only and 4,144 (58%) patients underwent SLNB plus CLND (Table 1). The average age overall was 57 years (SD: 15.9) and the cohort was predominantly white males (97% white, 59% males). Most patients had a Charlson-Deyo score of 0 (83%), had private insurance (56%), were from an urban location (95%), and went to HVCs (71%). Additional patient and facility characteristics are shown in Table 1. Tumor specific variables are summarized overall and by treatment group in Table 2. Most tumors had a Breslow thickness <4mm (72%) and the most common site was the trunk (38%). Ulceration and lymphovascular invasion were seen in 43% and 15% of cases, respectively. In univariate analysis, the two treatment groups significantly differed by many patient demographic, clinicopathologic, and facility factors (sex, payer, education, Charlson-Deyo score, year of diagnosis, facility region, facility type, facility volume, Breslow thickness, ulceration, primary tumor mitotic count, and primary site. (Tables 1&2). Overall observed trends in the number of CLNDs over time are shown in Figure 1. The total number of SNPM patients increased every year from 1,241 patients in 2012 to 1,703 in 2016. The proportion of SNPM patients undergoing CLND decreased over time from 63% in 2012 to 50% in 2016 (p<0.0001). The largest decrease occurred from 2015 to 2016 (-7%; 57% to 50%, respectively) and was greater than the decrease over the 4 prior years combined (-6%; 63% to 57%). Figure 2 shows trends in number of CLNDs over time stratified by HVC (Figure 2a) and non-HVC (Figure 2b). Overall, rates of CLND were higher in HVC (61%) as compared to
7
8 non-HVC (50%) (not shown in figure). The proportion of CLNDs decreased over time for both HVC (66.6% to 52.2%, p<0.0001) and non-HVC (54.6% to 50.3%, p=0.0597), but at greater magnitude in HVC (Figure 2). Table 3 shows results of the Poisson regression model with estimated relative risks of CLNB for several patient, facility, and pathologic factors. Factors that decreased likelihood of CLND were year of diagnosis (RR in 2016 vs 2012: .802; 95% CI: 0.742,0.865; overall p<0.0001) and increasing age (RR: 0.988; 95% CI: 0.985,0.99; p=0.0007). Factors that significantly increased the likelihood of CLND were ulceration (RR: 1.066; 95% CI: 1.012,1.122, p=0.02), increasing Breslow depth (RR:1.015; 95% CI: 1.004,1.025; p=0.006), anatomic location anywhere but lower extremity (RR: 1.28-1.31; p<0.0001) and treatment at HVCs (RR: 1.18; 95% CI: 1.099, 1.266; p<0.0001). Facility region (overall p<0.0001) was associated with CLND but rural/urban status and travel distance were not. Discussion: Recently reported randomized controlled trials have demonstrated that patients with SNPM may be able to forgo CLND and undergo observation alone with no detrimental effect on overall or melanoma specific survival (21–23). Our analysis shows that patients with SNPM captured in the NCDB are increasingly likely to have CLND omitted as part of their care, a trend that accelerated in 2015, the first year prospective randomized data were reported, and continued in 2016. We found that the proportion of patients with SNPM undergoing CLND decreased over time from 63% to 50% from 2012 to 2016, with the largest change from 2015-2016, a magnitude which was larger than the difference between all other years combined. Our study is similar to the recent analysis by Hewitt and colleagues, which examined data from years prior to release of the RCT results (27). Our cohort of patients was slightly different
8
9 as our study excluded patients with a prior cancer, those who died within 90 days, and those treated with palliative intent. Despite these differences, the overall rate of CLND utilization was similar between their study and ours (57.0% vs 58%, respectively). We also find increases in the total number of patients with SNPM over time. The treatment of advanced melanoma requires a multi-modal and multi-disciplinary approach (5), and treatment at HVCs is associated with improved survival in melanoma (28, 29). Thus, the trend in our data may be reflective of increasing referral from community settings and non-CoC facilities (not captured by the NCDB) to more specialized centers over time. This is supported by data demonstrating the increase in SNPM volume over time was primarily in HVCs compared to non-HVCs (Figure 2). We additionally examined factors associated with CLND. Similar to other analyses, we find that older age is associated with a lower likelihood of undergoing CLND (7, 11, 27, 30, 31). This may be due to both patient refusals to undergo the procedure and surgeons advising against a potentially morbid operation in an elderly patient (32). We also find no association of sex and likelihood of CLND, consistent with other data (11, 27, 32). Tumor location, especially in the lower extremity, is often associated with lower likelihood of CLND in SNPM, likely due to the increased morbidity of the procedure (7, 27, 31, 32), and we find similar results. This effect did not significantly change over time. Other tumor pathologic factors associated with CLND were Breslow depth and ulceration. There are multiple studies examining clinicopathologic factors associated with nonsentinel node positivity on CLND, and a 2013 meta-analysis showed that tumor ulceration was associated with a significantly higher odds of additional non-SLN positivity while Breslow depth was found to be equivocal (16). Other studies have found Breslow depth to predict additional
9
10 non-SLN positivity (10, 33). Multi-variate analysis from MSLT-II showed Breslow depth and ulceration were associated with worse melanoma specific survival for both the observation and the CLND arms (23). Previous studies have shown that thicker primary tumors and those with ulceration have an increased risk of hematogenous metastasis (34), thus the prognostic significance of these factors is likely independent of their effect on additional regional node burden. Prior studies have examined the association of facility melanoma volume on CLND in SNPM with conflicting results (7, 27). Using NCDB data from 2004-2005, Bilimoria et al found that patients treated at lower volume facilities had lower odds of CLND in SNPM, while Hewitt et al found no effect of hospital volume using NCDB data from 2012-2015. These studies both used total melanoma case volume while our study used the number of melanoma sentinel node procedures to define HVCs. By using the number of SLNBs to define hospital volume rather than total surgical case volume, this may be more sensitive to the association of hospital volume on regional node procedures. We found hospitals performing >15 SLNBs per year were more likely to utilize CLND. HVCs may be more likely to utilize CLND if they are referred more advanced cases with heavier regional node burden, but it is difficult to assess this hypothesis without data on the sentinel node tumor burden. Utilization in both HVCs and non-HVCs decreased over time, a magnitude that was greater in HVCs. This may reflect a more rapid incorporation of the randomized trial data into clinical practice in high volume, academic centers. Geographic and regional variations in treatment patterns are prevalent in melanoma, as well as multiple other cancers (35–37). Cormier and colleagues (11), in an analysis of SEER data from 1998-2001, found that the odds of guideline concordant management in melanoma overall
10
11 and by stage varied significantly by SEER registry. Using the NCDB, we found an overall effect of census region in the use of CLND. The explanation for this is likely complex and may be partly due to differences in underlying patient and physician/health system factors (38, 39), and is worth further study in melanoma specifically to determine barriers to treatment standardization and the diffusion of clinical trial data into surgical practice. The study has several limitations. Most importantly, as Hewitt and colleagues (27) have noted, it is difficult to determine from NCDB data (even after updating the sentinel node procedure coding in 2012) exactly who should undergo CLND in SNPM, as there is no variable that defines the size or volume of sentinel node disease burden. This is important to consider since both the DeCOG-SLT and MSLT-II trials included significant proportions of patients with very small tumor burden in the sentinel node. In both studies, 66% of patients had a SLN metastasis no larger than 1mm in size, a finding that should be taken into account when considering optimal management for individual patients with SNPM. Without the sentinel node data, we cannot determine whether the appropriate patients are being offered observation and/or if trial results are being overextended to patients with a larger sentinel node burden. Other limitations include the fact that NCDB is a hospital-based cohort rather than a population-based sample. As a result, we cannot account for practice patterns in facilities that are not CoC accredited. Additionally, we cannot account for time trends in CLND prior to 2012 as the needed data were not available before that time. Lastly, there were 1,064 cases with missing data for both facility type and facility region, which could affect the findings of regional variation in practice patterns. Conclusion:
11
12 We found declining rates of CLND in SNPM which increased in 2016, corresponding to initial reports of prospective, randomized data suggesting limited benefit to CLND. Several patient, clinical, and pathologic characteristics were associated with the likelihood of CLND, and there is regional variation in practice patterns, although regardless of practice setting, procedural volume was most associated with change in practice pattern. While this demonstrates early dissemination of clinical trials data, it is likely that greater change will be seen beginning in 2017/2018, reflecting reporting of the MSLT-II trial. Regardless, it will be important to continue to disseminate this information and standardize the patient cohort who are offered observation versus CLND, as it is likely that there remains a population of patients with SLN positive melanoma who still benefit from CLND.
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13 References: 1. Van Der Ploeg APT, Haydu LE, Spillane AJ, et al. Outcome following sentinel node biopsy plus wide local excision versus wide local excision only for primary cutaneous melanoma: Analysis of 5840 patients treated at a single institution. Ann Surg 2014;260:149–157. 2. Morton D, Thompson JF, Cochran A, et al. Sentinel-Node Biopsy or Nodal Observation in Melanoma. N Engl J Med 2006;355:1307–1317. 3. Morton DL, Thompson JF, Cochran AJ, et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med 2014;370:599–609. 4. Wong SL, Balch CM, Hurley P, et al. Sentinel lymph node biopsy for melanoma: American society of clinical oncology and society of surgical oncology joint clinical practice guideline. Ann Surg Oncol 2012;19:3313–3324. 5. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Cutaneous Melanoma 2019. Available at: https://www.nccn.org/professionals/physician_gls/pdf/cutaneous_melanoma_blocks.pdf. Accessed September 30, 2019. 6. National Comprehensive Cancer Network. Clinical Practce Guidelines in Oncology: Cutaneous Melanoma 2016. Available at: https://www2.trikobe.org/nccn/guideline/skin/english/skin_melanoma.pdf. Accessed September 30, 2019. 7. Bilimoria KY, Balch CM, Bentrem DJ, et al. Complete lymph node dissection for sentinel node-positive melanoma: Assessment of practice patterns in the United States. Ann Surg Oncol 2008;15:1566–1576. 8. Bilimoria KY, Raval M V., Bentrem DJ, et al. National assessment of melanoma care using formally developed quality indicators. J Clin Oncol 2009;27:5445–5451.
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16 2014. Ann Surg Oncol 2019;26:1604–1612. 26. Commission on Cancer. Scope of Regional Lymph Node Surgery: A Review of Data Validity, Revised Coding Directives, and Agency Transition Plans. 2012. Available at: https://www.facs.org/~/media/files/quality%20programs/cancer/ncdb/scope%20regional%20lym ph%20node%20surgery.ashx. Accessed September 30, 2019. 27. Hewitt DB, Merkow RP, DeLancey JO, et al. National practice patterns of completion lymph node dissection for sentinel node-positive melanoma. J Surg Oncol 2018;118:493–500. 28. Huo J, Lairson DR, Du XL, et al. Hospital Case Volume Is Associated with Improved Survival for Patients with Metastatic Melanoma. Am J Clin Oncol Cancer Clin Trials 2016;39:491–496. 29. Cheraghlou S, Agogo GO, Girardi M. Treatment of primary nonmetastatic melanoma at high-volume academic facilities is associated with improved long-term patient survival. J Am Acad Dermatol 2019;80:979–989. 30. Kingham T, Panageas KS, Ariyan CE, et al. Outcome of Patients with a Positive Sentinel Lymph Node who do not Undergo Completion Lymphadenectomy. Ann Surg Oncol 2010;17:514–520. 31. Chu BS, Koffi W, Hoehn RS, et al. Improvement and persistent disparities in completion lymph node dissection: Lessons from the National Cancer Database. J Surg Oncol 2017;116:1176–1184. 32. Shah DR, Yang AD, Maverakis E, Martinez SR. Age-related disparities in use of completion lymphadenectomy for melanoma sentinel lymph node metastasis. J Surg Res 2013;185:240–244. 33. Schuitevoerder D, Bubic I, Fortino J, et al. Patients with sentinel lymph node positive melanoma: Who needs completion lymph node dissection? Am J Surg 2018;215:868-872.
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17 34. Faut M, Wevers KP, van Ginkel RJ, et al. Nodular Histologic Subtype and Ulceration are Tumor Factors Associated with High Risk of Recurrence in Sentinel Node-Negative Melanoma Patients. Ann Surg Oncol 2017;24:142–149. 35. Nattinger AB, Gottlieb MS, Veum J, et al. Geographic Variation in the Use of BreastConserving Treatment for Breast Cancer. N Engl J Med 1992;326. 36. Kasumova GG, Eskander MF, de Geus SWL, et al. Regional variation in the treatment of pancreatic adenocarcinoma: Decreasing disparities with multimodality therapy. Surgery 2017;162:275–284. 37. Sineshaw HM, Wu XC, Dana Flanders W, et al. Variations in receipt of curative-intent surgery for early-stage non-small cell lung cancer (NSCLC) by state. J Thorac Oncol 2016;11:880–889. 38. Wennberg JE, Fisher ES, Skinner JS. Geography and the debate over medicare reform. Health Aff 2003;22. 39. Keating NL, Landrum MB, Lamont EB, et al. Area-Level Variations in Cancer Care and Outcomes. Medical Care 2012;50:366–373.
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Table 1. Demographic, Clinical, and Facility Characteristics
Variable Sex, n (%) Male Female Race, n (%) White Black Other Missing Spanish/Hispanic origin, n (%) Non-Spanish; non-Hispanic Hispanic Unknown Age, y, mean (SD) Charlson-Deyo score, n (%) 0 1 2 3+ Primary payor, n (%) Not insured Private insurance/managed care Medicaid Medicare Other government Insurance status unknown Median income 2012-2016, n (%) Missing/unknown <$40,227 $40,227-$50,353 $50,354-$63,332 ≥$63,333 Percent no high school degree 20122016, n (%) Missing/unknown ≥17.6%
All (n=7,146)
SLNB Only (n= 3,002)
SLNB+CLND (n=4,144)
4192(59) 2954(41)
1691(56) 1311(44)
2501(60) 1643(40)
6926(97) 70(1) 63(1) 87(1)
2902(97) 35(1) 22(1) 43(1)
4024(97) 35(1) 41(1) 44(1)
p Value 0.0007
0.1624
0.8448 6788(95) 214(3) 144(2) 57.2 (15.9)
2848(95) 94(3) 60(2) 60.2 (16.2)
3940(95) 120(3) 84(2) 55.1 (15.3)
5915(83) 952(13) 184(3) 95(1)
2442(81) 419(14) 97(3) 44(1)
3473(84) 533(13) 87(2) 51(1)
0.0004 0.0066
<.0001 246(3) 3992(56) 394(6) 2322(32) 98(1) 94(1)
94(3) 1504(50) 144(5) 1181(39) 38(1) 41(1)
152(4) 2488(60) 250(6) 1141(28) 60(1) 53(1) 0.0626
90(1) 951(13) 1505(21) 1806(25) 2794(39)
38(1) 403(13) 626(21) 716(24) 1219(41)
52(1) 548(13) 879(21) 1090(26) 1575(38)
83(1) 947(13)
34(1) 440(15)
49(1) 507(12)
0.0072
18
19 10.9%-17.5% 1767(25) 703(23) 1064(26) 6.3%-10.8% 2219(31) 917(31) 1302(31) <6.3% 2130(30) 908(30) 1222(29) Urban/rural, n (%) Missing/unknown 183(3) 74(2) 109(3) Rural 142(2) 69(2) 73(2) Urban 6821(95) 2859(95) 3962(96) Travel distance, miles, median (IQR) 16.9 (7.6, 40.6) 15.0 (6.7, 35.2) 18.5 (8.2, 45.6) Year of diagnosis, n (%) 2012 1241(17) 461(15) 780(19) 2013 1337(19) 527(18) 810(20) 2014 1416(20) 543(18) 873(21) 2015 1449(20) 623(21) 826(20) 2016 1703(24) 848(28) 855(21) Facility location, n (%) Missing/unknown 1062(15) 364(12) 698(17) New England 329(5) 134(4) 195(5) Middle Atlantic 991(14) 476(16) 515(12) South Atlantic 1189(17) 547(18) 642(15) East North Central 1243(17) 463(15) 780(19) East South Central 390(5) 193(6) 197(5) West North Central 548(8) 212(7) 336(8) West South Central 354(5) 166(6) 188(5) Mountain 410(6) 146(5) 264(6) Pacific 630(9) 301(10) 329(8) Facility type Missing/unknown 1062(15) 364(12) 698(17) Community cancer program 333(5) 173(6) 160(4) Comprehensive community cancer program 1736(24) 821(27) 915(22) Academic/research program 3326(47) 1312(44) 2014(49) Integrated network cancer program 689(10) 332(11) 357(9) Facility volume Non-high-volume center (<15 sentinel node procedures/year) 2077(29) 1033(34) 1044(25) High-volume center (≥15 sentinel node procedures/year) 5069(71) 1969(66) 3100(75) SLNB, sentinel lymph node biopsy; SLNB+CLND, sentinel lymph node biopsy and completion lymph node dissection
19
0.1107
<.0001
<.0001
<.0001
<.0001
20
Table 2. Tumor Characteristics All (n=7,146)
SNLB (n= 3,002)
SNLB+CLND (n=4,144)
Characteristic Primary Site, n(%) Head and Neck 992(14) 394(13) 598(14) Skin of trunk 2720(38) 980(33) 1740(42) Skin of upper limb and shoulder 1563(22) 636(21) 927(22) Skin of lower limb and hip 1819(25) 971(32) 848(20) Unspecified 52(1) 21(1) 31(1) Breslow Thickness, n(%) .1 mm to 1 mm 907(13) 422(14) 485(12) 1.1 mm to 2 mm 2002(28) 856(29) 1146(28) 2.1 mm to 4 mm 2198(31) 886(30) 1312(32) ≥ 4.1 mm 1890(26) 763(25) 1127(27) Microinvasion, not documented, or unknown 149(2) 75(2) 74(2) Ulceration, n(%) No ulceration present 4062(57) 1753(58) 2309(56) Ulceration present 3084(43) 1249(42) 1835(44) Vascular Invasion Missing/Unknown 1130(16) 509(17) 621(15) Not present 4944(69) 2036(68) 2908(70) Present 1072(15) 457(15) 615(15) Primary Tumor Mitotic Count, n(%) 0 mitoses per square mm 488(7) 229(8) 259(6) 1 to 2 mitoses per square mm 2147(30) 894(30) 1253(30) 3 to 4 mitoses per square mm 1245(17) 539(18) 706(17) 5+ mitoses per square mm 2680(38) 1054(35) 1626(39) Missing 586(8) 286(10) 300(7) SLNB, sentinel lymph node biopsy; SLNB+CLND, sentinel lymph node biopsy and
p Value <.0001
0.0019
0.0242
0.3825
<.0001
completion lymph node dissection
20
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Table 3. Poisson Model Evaluating Factors Associated with Sentinel Lymph Node Biopsy and Completion Dissection vs Sentinel Lymph Node Biopsy Only
Variable, N=4815* Year of diagnosis 2013 2014 2015 2016 2012 Race American Indian/Alaska Native Asian/Pacific Islander Black White Sex Female Male Age, y Insurance Not insured Public insurance Private insurance/managed care Urban/rural Rural Urban Distance to facility (10-mile increments) Charlson-Deyo Score 1 2 3+ 0 Ulceration Yes No Lymphovascular invasion Present Not present Breslow depth (in mm) Facility type Community cancer program
Relative risk
95% CI
1.005 0.970 0.896 0.801 Reference
0.936,1.08 0.902,1.043 0.831,0.966 0.742,0.865
1.206 0.981 0.861 Reference
0.829,1.753 0.748,1.286 0.632,1.171
Overall p value <.0001
0.6034
0.211 0.968 Reference 0.988
0.921,1.019
0.907 0.970 Reference
0.792,1.038 0.912,1.031
0.985,0.99
<.0001 0.24
0.777 0.977 Reference
0.83,1.15
1.001
0.999,1.003
1.038 0.911 1.128 Reference
0.969,1.112 0.768,1.081 0.924,1.376
0.3775 0.2906
0.0154 1.066 Reference
1.012,1.122 0.2761
0.965 Reference 1.015
0.905,1.03 1.004,1.025
1.050
0.983,1.122
0.0058 0.1409
21
22 Academic/research program Integrated network cancer program Comprehensive community cancer program Facility region East North Central East South Central Middle Atlantic Mountain New England Pacific South Atlantic West North Central West South Central Facility volume ≥15 SLNBs per year <15 SLNBs per year Primary site Head and neck Skin of trunk Skin of upper limb and shoulder Unspecified Skin of lower limb and hip
0.942
0.82,1.083
0.968
0.88,1.064
Reference <.0001 1.109 0.910 0.909 1.124 1.047 0.971 0.967 1.091 Reference
0.977,1.259 0.778,1.065 0.793,1.041 0.976,1.294 0.896,1.223 0.841,1.12 0.849,1.101 0.953,1.25
1.180 Reference
1.099,1.266
<.0001
<.0001 1.278 1.314 1.300 1.400 Reference
1.17,1.395 1.225,1.408 1.204,1.403 0.966,2.029
*Patients with complete data included in regression analysis
22
23 Figure legend Figure 1. Overall time trends in surgical management of sentinel node positive melanoma. completion lymph node dissection use decreased over time, with the largest decrease from 20152016. Overall p-value for trend: <0.0001 Figure 2. Trends in surgical management of sentinel node positive melanoma over time in (A) high-volume centers and (B) low-volume centers. High-volume centers had a higher proportion of patients undergoing completion lymph node dissection (CLND) but had a larger decrease over the study period (overall p value for trend <0.001). Low-volume centers had a smaller proportion undergoing completion lymph node dissection CLND, but had a non-significant, smaller downward trend in CLND use (overall p value for trend p=0.06). SNPM, sentinel node positive melanoma
23
24 Precis Randomized trials have shown limited value of completion lymph node dissection in select patients with sentinel node positive melanoma. In an assessment of national practice patterns using the National Cancer Database, we identify significant declines in the use of completion lymph node dissection beginning shortly after randomized trial data was initially reported.
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